Design and synthesis of novel beta-lactam antibiotics

β-Lactam antibiotics are the dominant class of antibiotics used today. They exert their antibacterial activity by inhibiting a class of enzymes called penicillin binding proteins (PBPs). Bacteria developed resistance to β-lactam antibiotics by altering cell-wall permeability or PBPs, or producing β-lactam-hydrolizing enzymes called β-lactamases.; Antibiotics are among the most prescribed pharmaceuticals worldwide. These antibiotics are generally not metabolized in an animal body and survive in the environment for extended periods of time, which favor the selection of bacterial resistance. We designed and synthesized an antibiotic with a functionality that could be unmasked by light and the antibacterial property of the compound was therefore destroyed. This concept of design could be generalized to other classes of antibiotics.; The cell wall imparts structural strength and shape to bacteria. It is made up of polymeric glycan chains with peptide branches that are cross-linked to form the cell wall. The cross-linking reaction, catalyzed by transpeptidases, is the last step in cell wall biosynthesis. These enzymes are members of the family of penicillin-binding proteins (PBPs), the targets of β-lactam antibiotics. We report herein the structure of a PBP complexed with a novel cephalosporin designed to probe the mechanism of the cross-linking reaction catalyzed by transpeptidases. The 1.2 Å resolution X-ray structure of this cephalosporin bound to the active site of the bifunctional serine type D-alanyl-D-alanine carboxypeptidase/transpeptidase (EC 3.4.16.4) from Streptomyces sp. strain R61 reveals for the first time how the two peptide strands from the polymeric substrates are sequestered in the active site of a transpeptidase. The structure of this complex provides a snapshot of the enzyme and the bound cell wall components poised for the final and critical cross-linking step of cell wall biosynthesis. Two other related cephalosporins were also designed and synthesized. The X-ray structures of these cephalosporins bound to the active site of different types of PBPs are expected to be obtained in the near future.